JPS6218527B2 - - Google Patents

Description

[Detailed description of the invention]

PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions. The pharmaceutical composition consists of aggregates having a diameter of less than 20,000 A, the aggregates comprising as component (a) at least one ergot peptide alkaloid and as component (b) at least one pharmaceutically acceptable ethoxylated cholesterin. Component (b) has an average HLB of 10 to 30 and is present at least 10 times as much by weight as component (a). Component (a) is known to be poorly absorbed into the blood when administered enterally, for example orally. Such poorly absorbed active agents have a cumulative absorption rate in the human body of up to 45%, e.g. 35%, according to standard tests.
or less than 25%. For example, an aqueous solution of approximately 0.008% (weight/volume) test substance is administered orally to bile fistula rats. The cumulative excretion rate of the substance in bile and urine is determined by conventional methods. The dosage of the substance is appropriately selected so that the cumulative absorption rate essentially levels out after 48 hours. In the same test, the initial rate of excretion of the substance, for example in the bile, is determined in a conventional manner. Compared to other compositions, the composition exhibits significant resorption properties as evidenced by greater cumulative and initial absorption rates in standard tests. Therefore, the present composition is indicated where it is desired to achieve high blood concentrations as quickly as possible. Examples of component (a) include, for example, ergotamine or hydrogenated ergot peptide carcaloids (e.g. dihydroergotoxine, dihydroergocristine, 13-bromine derivatives thereof; dihydroergonine, dihydroergocriptine, dihydroergotamine, etc.); 13-brome derivatives; dihydroergocornine, dihydroergobaline). The active agent content naturally varies over a wide range and depends on the type of active agent used and the condition to be treated;
The dosage can be adjusted to the desired dosage depending on the dosage and dosage form of the preparation. However, to obtain an individual therapeutic effect, the amount of active agent per administration in the compositions of the present invention may be lower than the amount of the same active agent required in conventional formulations used to achieve the same effect. . Ingredient (a)
is 5% by weight of the formulation in solid form in the case of a single dosage form.
For example, up to 2.5% by weight, and in the case of solutions up to 1% by weight of the formulation. for example,
For drops an amount of 0.05-0.6% is preferred, for tablets and capsules 0.2-4.0%, especially 0.2-2.5%
For example, amounts of 0.4 to 2.5% are preferred. The HLB value (component b, lipophilic balance value) is a measure of the relative proportion of hydrophilic groups in emulsifier molecules.
Act. Helv.) 44, 9 (1969) and HP Fiedler,
Hilfstoffe fu¨r Pharmazie), Kosmeteiku und Angrenzende Gebito,
P. 263, Edeithiocantor KG, 1971] Physiologically acceptable ethoxylated cholesterin having an average HLB value of 10 to 20 (especially 12 to 16) is preferred. A suitable ethoxylated cholesterin is, for example, cholesterin ethoxylated with about 24 moles of ethylene oxide (Sollan C24®, American Cholesterol Company). Emulsifiers such as oxyethylene-oxypropylene polymers can also be present. These include, for example, polymers with an average molecular weight of about 1000 to 10000, such as 40% polyoxyethylene, and oxyethylene-oxypropylene polymers (Pluronik L64 (registered trademark, Wyandt Chemicals)) with an average molecular weight of about 2900. ) average molecular weight is approximately 3500
oxyethylene-oxypropylene polymer (Pluronic P68 (registered trademark, Wyandot Chemicals)) or polyoxyethylene content
It is an oxyethylene-oxypropylene polymer (Pluronik F68 (registered trademark, Wyandot Chemicals)) having an average molecular weight of about 8,700. It is convenient to construct components (a) and (b) described below using emulsifiers of various types depending on their chemical and physical properties, molecular size and shape. The amount of emulsifier (including ethoxylated cholesterin) used depends on the emulsifier used, especially its chemical and physical properties, the quality and amount of adjuvant used, and the degree of improvement in absorption desired. The upper limit for the amount of emulsifier used will of course depend on the physiological tolerance of the emulsifier, optionally taking into account the expected duration of treatment and frequency of administration. Preferably, the ingredients in the compositions of the invention are present in such amounts that the total amount of component (b) does not exceed 50 mg/unit dose. The weight ratio of component (b) total amount: component (a) is, for example, 10:1 ~
The ratio is 50:1, preferably 20:1 to 30:1. In anhydrous dosage forms, the total amount of emulsifier may be up to 60%, preferably up to 60%, in the unit dosage formulation.
It is 20-50%. For water-containing preparations, the concentration of component (b) is conveniently determined by the CMC (critical micelle concentration) of the emulsifier used.
MAC (maximum additive concentration). The total amount of component (b) in the aqueous dosage form is preferably 1 to 5% by weight. Contains a pharmacological base, preferably a lipoid base
As (c), it may be conveniently included in the aggregate. The amount of component (c) is 25 times (preferably 10 times) the amount of component (a).
It is preferable that the amount is as follows. Lipoid bases that can be used include, for example (C ₆ -
_C20 ) monohydric or polyhydric ( _C2 - _C6 ) alcohols, preferably alcohols with 2 to 3 carbon atoms, partially or fully esterified with aliphatic carboxylic acids;
In particular glycerin or propylene glycol or their condensates (eg polyglycerin). For the production of solid dosage forms, it is convenient to use lipoid bases that are solid at room temperature; for the production of liquid dosage forms, it is convenient to use liquid lipoid bases or mixtures of solid and/or liquid lipoid bases that are liquid at room temperature. It is convenient to use. Particularly suitable solid lipoid bases are only partially esterified alcohols, especially saturated mono- and diglycerides. The aliphatic carboxylic acids contained in the solid esters can preferably contain 12 to 20 carbon atoms, can be straight-chained or branched and can have hydroxyl groups. Particularly suitable for the preparation of solutions are fully esterified alcohols, especially triglycerides, such as esters of unsaturated or saturated carboxylic acids (preferably containing 8 to 12 carbon atoms). Examples of suitable esters are, in particular, mono-, di- or triglycerides of saturated or unsaturated fatty acids, such as glycerol monolaurate, monomyristate,
Monooleates or monoricinolates, peanut oil, oily triglycerides or propylene glycol esters of saturated vegetable oil fatty acids containing 8 to 12 carbon atoms, such as propylene glycol monostearate. The non-aggregated portion of the composition further contains the active agent and a pharmacological carrier or diluent (component d) that does not interfere with the formation of ethoxycholesterin-containing aggregates or impair the stabilization of the resulting aggregates. can do. For example, it is convenient to add a water-soluble solid or liquid physiologically acceptable monohydric or polyhydric alcohol. Suitable alcohols include, for example, ethanol, propylene glycol, glycerin, sugar alcohols and those having an average molecular weight of, for example
300-10000 polyethylene glycol. The addition of polyhydric alcohols (e.g. polyethylene glycol), which promote the solubilization of poorly water-soluble active agents, may be useful if the emulsifier mixture used contains no or only small amounts of oxyethylene-oxypropylene polymers. Particularly desirable. When producing a liquid formulation, it is preferred to add liquid alcohols, such as lower monohydric or polyhydric alcohols and/or polyethylene glycols having an average molecular weight of 2000 or less, preferably 300 to 1500. For solid formulations, it is convenient to use alcohols that are solid at room temperature, such as sugar alcohols and/or polyethylene glycols with an average molecular weight of 1800 or more, preferably 2000 to 10000, especially 5000 to 7000. The water-containing composition of the invention may be 20 to 95% by weight, e.g.
90% by weight preferably 30-70% by weight, for example 30-
It can contain 50% by weight of water and optionally other adjuvants. The alcohol content of the aqueous solution is, for example, from 0 to 50% by weight of the formulation, preferably from 20 to 40%. Anhydrous liquid formulations contain the active agent and ethoxylated cholesterin finely dispersed in a water-soluble and/or water-dispersible liquid base comprising one or more liquid bases and optionally other adjuvants. Contains aggregates. Particularly suitable liquid bases are physiologically acceptable lower mono- or polyhydric alcohols and/or liquid polyethylene glycols (e.g. polyethylene glycols with an average molecular weight below 2000).
It is. The liquid composition may contain as other ingredients other pharmaceutical adjuvants such as preservatives and flavoring agents and buffers.
can also be included. Liquid formulations can also contain physiologically acceptable water-soluble and/or water-dispersible solid substances, especially if it is desired to form them into solid dosage forms. The solid dosage form of the present invention comprises an active agent finely dispersed in a base formed of one or more water-soluble and/or water-dispersible solid substances and optionally other pharmaceutical adjuvants. Contains cholesterin-containing aggregates. Suitable physiologically acceptable water-soluble solid substances are, for example, polyethylene glycols that are solid at room temperature (preferably polyethylene glycols with an average molecular weight of about 2000 to 10000, particularly preferably 6000 to 10000), polyvinylpyrrolidone, solid oxyethylene glycols, etc. Oxypropylene polymers, sugars (eg lactose), sugar alcohols (eg mannite or sorbitol) and carboxymethylcellulose. The water-dispersible solid material is preferably used in the form of a finely dispersed powder so that due to its large surface area it can absorb the finely distributed active agent- and ethoxylated cholesterin-containing aggregates.
Suitable solid substances are physiologically acceptable, water-dispersible, non-swellable, inorganic and/or organic bases, provided that they do not irreversibly bind the active agent used. Suitable inorganic bases are, for example, dicalcium phosphate or tapped
Finely powdered silicic acid (especially wet precipitated silicic acid) with a volume of preferably 250 to 1000 c.c./100 g. Depending on the desired formulation, the solid formulation may contain as other ingredients physiologically acceptable pharmaceutical adjuvants (e.g. preservatives and flavoring agents) and any desired tablet adjuvants ordinarily used in the manufacture of tablets or suppositories. It can also include any desired suppository base used. The active agent-containing aggregates have a diameter of less than 20,000 Å;
Preferably 100-10000Å, particularly preferably 2000Å
It has a diameter of 400 Å or more. In aqueous formulations, it is preferred that the emulsifier- and active agent-containing aggregates be very finely dispersed in the aqueous liquid, resulting in a clear or only slightly proteinaceous liquid. The diameter of the active agent- and emulsifier-containing aggregates is preferably less than 2000 Å, particularly preferably 1000 Å or less.
Å or less. The anhydrous solid or liquid compositions of the present invention preferably contain very finely distributed active agent-containing aggregates such that when placed in an aqueous medium, the poorly absorbed active agent becomes active in a finely dispersed form. It is a solid or liquid formulation that rapidly forms a clear or slightly proteinaceous liquid which is solubilized in the form of drug- and ethoxylated cholesterin-containing aggregates. The novel compositions of the present invention may be liquid or solid;
Preferably it is administered orally. The liquid formulations of the invention can be administered, for example, as drops or syrup. Anhydrous liquid formulations can also be filled into soft gelatin capsules to form unit dosage forms.
Preferred water-containing formulations are drops. Suitable solid dosage forms are, for example, powders, granules, capsules, tablets or film-coated tablets for oral administration, or rectal suppositories. Preferred compositions of the invention are liquid or preferably solid formulations of ergot peptide alkaloids, the total amount of polyhydric alcohol and emulsifier being preferably 15-80%, for example 70% by weight of the total formulation in the case of aqueous formulations; 40-99 of the total formulation in case of anhydrous formulations
%. This composition can be obtained by a method comprising the step of formulating an aggregate having a diameter of 20,000 Å or less, consisting of components (a) and (b) as defined above. The liquid composition of the present invention comprises component (a) and component (b).
in a liquid base (e.g. an anhydrous medium or water or a hydrous medium), preferably using ultrasound and/or a high speed stirrer, optionally with other pharmaceutical adjuvants. can do. According to one embodiment of the process of the invention, the active agent is first dissolved in a surfactant with slight heating, optionally with the addition of a lipoid base, and this mixture is then dissolved in a liquid base. Dilute and homogenize by ultrasonication or high speed stirring. The solid composition of the present invention can also be prepared by carefully removing the liquid base (e.g. water and/or lower alcohol) from the initially prepared liquid formulation and preparing the resulting powdery or spongy porous dry product using known methods. It can be manufactured by formulating the desired dosage form. Careful drying of the solutions can be carried out in known manner, for example by freeze-drying or spray-drying. For example, the liquid formulation can be frozen at a temperature of -80° to -50°C and then freeze-dried in a high vacuum, or the liquid can be sprayed into a drying chamber and dried with hot air (e.g. at a temperature of 120° to 180°C). can do. If desired, the resulting dry product can then be filled into capsules, granulated and compressed by known methods, optionally with the addition of suitable pharmaceutical adjuvants such as tablet adjuvants and suppository bases. It can be made into tablets or suppositories. All aggregates formed are less than 20,000 Å in diameter. To avoid unstable milky emulsions,
It is necessary that the dimensions of the aggregates be within certain limits. That is, it has been found that for the aggregates to be suitable, the particle size should be less than 20,000 Å. In addition, it is generally known that when the particle size is larger than 10000 Å, it shows a milky white appearance, when it is 100 Å to 500 Å or less, it becomes transparent, and in the range centered around 1000 Å in between, it shows a bluish-white appearance. Next, examples of the present invention will be shown, and all temperatures in the examples are expressed in degrees Celsius. Polytron is a trademark. Examples 1-17: Water-containing drops of poorly absorbed active agents The formulations of Examples 1-17 having the compositions shown in Table 1 below are prepared as follows. The ergot peptide alkaloids are dissolved in an emulsifier and lipoid base (if used), with a portion of the polyhydric alcohol added if necessary, and heated slightly (30
(at a temperature of ~50°). To the above solution, while vigorously stirring with a Polytron homogenizer, water or an aqueous solution of other adjuvants or a mixture of water and the polyhydric alcohol used is added, and the resulting mixture is subjected to ultrasonication and/or
Homogenize by treating with a Polytron homogenizer for 5-6 minutes. The resulting homogeneous solution is filled into a dropper bottle. This product contains aggregates with a particle size of less than 20,000 Å, as evidenced by its blue to milky white color. Emulsifier name Manufacturer a Sollan C24 American Cholesterol Co. b Pluronic L64 W&D Chemicals c Pluronic F68 W&D Chemicals d Milji 52 Atlas Chemical Industries e Miglyol 812 Henkel f Aerosol OT American Cyanamids

【table】

[Table] Example 18: Drops containing dihydroergotamine 60 mg of dihydroergotamine mesylate was added to about 24 moles of ethylene oxide adduct of cholesterin ^a)
pH4.1 with sodium acetate/acetate buffer with 1.5g
Fill a dropper bottle with 60 c.c. of water adjusted to 100 ml and homogenize with a Polytron homogenizer to obtain a clear liquid. Example 19: Anhydrous drops containing dihydroergotamine a) 2 g of dihydroergotamine are added with 50 g of an approximately 24 mole ethylene oxide adduct of cholesterin ^a) to 500 g of polyethylene glycol 400 heated to 50° in a water bath and treated with ultrasound for 5 minutes, Fill a dropper with the resulting clear liquid. b. 250g polyethylene glycol 400 and 250g instead of 50g polyethylene glycol 400
The operation described in a) above is performed using glycerin. Example 20: Soft gelatin capsules containing dihydroergonine.
24 mole ethylene oxide adduct ^a) Add to 150 c.c. of polyethylene glycol 300 heated in water solution at 50° with 75 g and treated with ultrasound. The resulting clear liquid is then poured into soft gelatin capsules for 100ml
Fill in the amount of mg/capsule. Example 21: Capsules containing dihydroergocristine 300 mg of dihydroergocristine with approximately 24 mole ethylene oxide adduct of cholesterin ^a) 1.7 g
and 30 g of a 22% aqueous solution of oxyethylene-oxypropylene polymer ^c) having an average molecular weight of 8700, heated to 40° and dissolved with 1.2 g of glycerin monolaurate.
Add and homogenize. After adding 50 c.c. of water, it is rapidly frozen in a rotating flask at -80° and freeze-dried under high vacuum. As freeze-drying progresses, the dried material is gradually heated to 25-30°. The resulting dry product is then filled into capsules in an amount of 50 mg/capsule. Example 22: Capsules Containing Dihydroergotamine 30 mg of dihydroergotamine is approximately
24 mole ethylene oxide adduct ^a) Dissolve 750 mg in 50 c.c. of absolute ethanol and stir this solution in vacuo for 30 molar
Dry by evaporation at °. Homogenize the residue with a Polytron homogenizer for about 5 minutes, during which time 100 c.c. of distilled water is gradually added. 225 mg of highly dispersed silicic acid ^g) are suspended in the clear liquid obtained and the suspension is homogenized by sonication at 30° for 3 minutes. This suspension is frozen at -80° and then freeze-dried. The lyophilized product is filled into gelatin capsules in an amount of 100 mg/capsule. Example 23: Lyophilized product containing dihydroergovaline in a freeze-dried ampoule 400 mg of dihydroergovaline was mixed with about 24 mole ethylene oxide adduct of cholesterin ^a) 10 g and
Dissolve in 300 c.c. of absolute ethanol with 2000 g of polyethylene glycol. The solution is evaporated to dryness in a rotary evaporator at 30° and 200 c.c. of distilled water is gradually added to it while constantly homogenizing the residue with a Polytron homogenizer.
The resulting clear micellar solution of the active agent is placed in ampoules (2 mg of dihydroergovaline in 1 ampoule).
After filling, the ampoule is rapidly lyophilized at −80° and then sealed in vacuo. In addition, dry preparations having the compositions shown in Table 2 below were produced in the same manner as those described in Examples 21 to 23,
It can also be filled into capsules or dry ampoules, or granulated and/or tableted with the addition of suitable galenic adjuvants. The solutions obtained after homogenization, homogenization, or sonication in Examples 18-36 are all clear and therefore contain aggregates with a particle size of about 5000A or less. g Silicic acid K320 manufactured by Degutsusa (tamped volume approx.
500c.c./100g) h Sollan C16 manufactured by American Cholesterol
(Registered Trademark) i PVP K30 (registered trademark) manufactured by Vasissier Anilinund Sodafabrik GmbH j Primosiel (registered trademark) manufactured by Scholtens Hemitschief Abrikken K Brij 56 (registered trademark) manufactured by Atlas Chemical Industries GmbH

【table】

Claims (1)

[Scope of Claims] 1 Consists of aggregates with a diameter of 20,000 Å or less; the aggregates contain as component (a) at least one ergot peptide alkaloid and as component (b) at least one pharmaceutically acceptable 1. A galenic preparation for enteral administration, comprising ethoxylated cholesterin; component (b) has an average HLB value of 10 to 30, and is present at least 10 times as much by weight as component (a). 2. The galenic preparation according to claim 1, wherein the ergot peptide alkaloid is dihydroergotamine or dihydroergotoxin.